Genetic analysis of radiation-induced changes in human gene expression

Abstract

Humans are exposed to radiation through the environment and in medical settings. To deal with radiation-induced damage, cells mount complex responses that rely on changes in gene expression. These gene expression responses differ greatly between individuals and contribute to individual differences in response to radiation. Here we identify regulators that influence expression levels of radiation-responsive genes. We treated radiation-induced changes in gene expression as quantitative phenotypes, and conducted genetic linkage and association studies to map their regulators. For more than 1,200 of these phenotypes there was significant evidence of linkage to specific chromosomal regions. Nearly all of the regulators act in trans to influence the expression of their target genes; there are very few cis-acting regulators. Some of the trans-acting regulators are transcription factors, but others are genes that were not known to have a regulatory function in radiation response. These results have implications for our basic and clinical understanding of how human cells respond to radiation.

Figure 1. Individual variation in gene expression response to ionizing radiation

Fold change in 11 radiation-responsive genes; data for each individual are shown as a circle (open circles for 2-h-after-irradiation expression phenotypes; filled circles for 6-h-after-irradiation expression phenotypes). TRIAP1 (TP53-regulated inhibitor of apoptosis 1) is shown as an example of a gene that showed little individual variation in response to ionizing radiation. Other genes show extensive individual variation in gene expression.

Figure 2. Genome scans for four expression phenotypes

The chromosomal location of the target gene is given in parentheses. a, Example of 2-h-after-irradiation expression phenotypes. b, Example of 6-h-after-irradiation expression phenotypes.

Figure 3. Results of knockdown of five regulators of radiation-expression phenotypes

Regulators of expression levels of radiation-responsive genes were knocked down by siRNAs. Changes in expression levels of the regulators and their corresponding target genes after knockdown of the regulators are shown, as are changes in expression levels of a control gene (encoding glyceraldehyde-3-phosphate dehydrogenase) after knockdown of the regulators. Data are shown as means ± s.e.m. for four or more independent transfections. Asterisk, P < 0.05; two asterisks, P = 0.07; no symbol, P > 0.05.